WO 2005/037843 describes partially saturated quinazolines anellated with heteroaryls as kinase inhibitors.
WO 2012/010704 describes 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
The aim of the present invention is to provide new compounds which can be used for the prevention and/or treatment of diseases characterised by excessive or abnormal cell proliferation. The compounds according to the invention are characterised by a powerful inhibitory effect on the phosphorylation activity of the IGF-1 receptor (IGF1-R) and insulin receptor (IR) located in cell membranes and a potent efficacy against tumour cells, e.g. glioblastoma, colorectal cancer etc., which is mediated through the inhibition of phosphorylation of the receptor. In addition to the inhibitory effect and cell activity the compounds have acceptable solubility, PK properties and selectivity over other kinases (Invitrogen panel).
The insulin-like growth factor (IGF) and insulin signalling network is a highly conserved and essential pathway involved in biological processes including growth, metabolism and homeostasis. In addition, deregulated signalling via this network can enhance tumorigenesis and metastasis of certain cancers.
The ligands IGF-1, IGF-2 and insulin are highly homologous and activate specific hetero or homodimers of the IGF-1R and IR. Following ligand binding, the IGF-1R and IR undergo autophosphorylation mediated via the receptor tyrosine kinase domains. The phosphorylated receptors activate the canonical Ras-Raf-MEK-ERK1/2 and PI3K-PDK1-Akt intracellular signaling cascades, which leads to cell proliferation and survival. In addition, activation of the IR by insulin stimulates the uptake of glucose and storage of glycogen in metabolic tissues such as the liver, adipose and muscle.
Published research articles as well as medical and epidemiological investigations have identified a strong correlation between expression of the IGF-1R and IR and ligands for these receptors in tumor development and progression. Developing a small molecule competitive inhibitor of the ATP-binding pocket of the IGF-1R and IR as a means of blocking growth and survival signaling cascades in cancer is therefore desirable. The anticipated clinical benefit of blocking such an interaction would be to reduce tumor growth rate and potentially sensitize tumors to cytotoxic agents or targeted therapies.